Project Summary Over the past decade, the NIDDK IBDGC (Inflammatory Bowel Disease Genetics Consortium) has generated extraordinary datasets in support of genetic analysis of the onset, progression, and therapeutic response to Crohn's disease and ulcerative colitis. This Ancillary project will complement ongoing IBDGC research by providing parallel statistical genetic analyses focused on transcriptomics, while also developing a novel strategy for genetic manipulation of patient-derived epithelial cells. There are four major biomedical genomics focus areas addressed by the research, namely fine mapping of loci influencing inflammatory bowel disease, elucidation of the cell and molecular function of causal genes, understanding how polymorphism influences pathology, and translating quantitative genetic discoveries into clinical outcomes. Specifically, integrative genomics expertise will be used to refine the credible intervals responsible for complex association signals at individual loci, enhance transcriptional risk scores (TRS) that have recently been shown to provide much greater prediction of disease and progression than genetic risk scores, and explore the potential of in silico predicted transcriptome-wide association studies in the context of IBD. These studies will utilize the IBDGC datasets through collaborative arrangements mediated by data coordinating center. In addition, proof of principle for the use of lipid nanoparticles as an efficient and specific delivery system for genome editing and/or pharmaceutical delivery to targeted cell types in gut- derived organoids will be demonstrated. Single cell RNA-Seq will be used to partition variability in gut epithelial gene expression in the half dozen most common organoid cell types into contributions of the ethnicity, location of the biopsy, type of disease, and source laboratory. This data will serve as a foundation for evaluating the effects of a half dozen gene knock-outs across cell types using the lipid nanoparticle delivery system. All analyses and reagents will be made available to consortium members as expected for collaborative IBDGC research.